Outcomes among oropharyngeal and oral cavity cancer patients treated with postoperative volumetric modulated arctherapy

Background Presently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique. This study aimed to assess the oncological outcomes of this population treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure. Material and methods Between 2011 and 2019, 167 patients were included (40% of oropharyngeal cancers, and 60% of oral cavity cancers). The median age was 60 years. There was 64.2% of stage IV cancers. All patients had both T and N surgery. 34% had a R1 margin, 42% had perineural invasion. 72% had a positive neck dissection and 42% extranodal extension (ENE). All patients were treated with VMAT with simultaneous integrated boost with three dose levels: 66Gy in case of R1 margin and/or ENE, 59.4-60Gy on the tumor bed, and 54Gy on the prophylactic areas. Concomittant cisplatin was administrated concomitantly when feasible in case of R1 and/or ENE. Results The 1- and 2-year loco-regional control rates were 88.6% and 85.6% respectively. Higher tumor stage (T3/T4), the presence of PNI, and time from surgery >45 days were significant predictive factors of worse loco-regional control in multivariate analysis (p=0.02, p=0.04, and p=0.02). There were 17 local recurrences: 11 (64%) were considered as infield, 4 (24%) as marginal, and 2 (12%) as outfield. There were 9 regional recurrences only, 8 (89%) were considered as infield, and 1 (11%) as outfield. The 1- and 2-year disease-free survival (DFS) rates were 78.9% and 71.8% respectively. The 1- and 2-year overall survival (OS) rates were 88.6% and 80% respectively. Higher tumor stage (T3/T4) and the presence of ENE were the two prognostic factors significantly associated with worse DFS and OS in multivariate analysis. Conclusion Our outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are encouraging, with high rates of loco-regional control. However, the management of ENE still seems challenging.


Introduction
Surgery is one of the cornerstone treatments for oropharyngeal and oral cavity cancers (1).Adjuvant postoperative radiation therapy is recommended for patients with adverse features, including advanced disease and inadequate margins.The addition of concomitant chemotherapy is recommended, particularly for patients who have 'high risk' pathological features including extranodal extension (ENE) and/or a positive surgical margin (1, 2).
Intensity Modulated Radiation Therapy (IMRT) or Volumetric Modulated Arctherapy (VMAT) is today the recommended radiation technique for the treatment of head and neck cancers (3).IMRT/VMAT for head and neck cancers is a complex technique both for target volume delineation and treatment planning (4,5).The delineation of the target volumes is an essential step conditioning the results of the treatment, particularly in terms of loco-regional control (6)(7)(8)(9).Presently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique.This study aimed to assess the oncological outcomes of operated patients with oropharyngeal and oral cavity squamous cell carcinomas (SCC), treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure.

Patients
The database maintained by the Department of Radiation Oncology at our institution was used to identify patients treated with postoperative VMAT for oropharyngeal or oral cavity SCC from May 2011 to December 2019.Patients with distant metastases or concomitant malignancies at the time of diagnosis, histology other than SCC, R2 margins, and/or a previously irradiated cancer of the head and neck were excluded.
One hundred and sixty-seven patients were retrospectively reviewed.Patient characteristics are described in Table 1.

Treatment
The overall treatment strategies were individualized for each patient following recommendation by a multidisciplinary tumor board.

Surgery
All patients included underwent surgery on the primary tumor accompanied by lymph node dissection (unilateral for 46.1% and bilateral for 53.9%).The operative technique depended on the location and initial extension of the disease.Sixty-seven patients (40%) had a free flap inserted during surgical reconstruction.

Radiotherapy
Patients underwent radiotherapy in case of advanced tumors (T3-T4), close or positive margins, lymph node involvement with or without ENE, the presence of lymphatic-vascular space invasion, and/or PNI (10,11).The median interval from surgery to initiation of radiotherapy was 46 days (24 -100).All patients were irradiated with VMAT (Rapidarc®, Varian Medical Systems, Palo Alto, CA, USA) with simultaneous integrated boost (SIB).A planning CTscan, supine, in the treatment position, was performed, with 2.5mm-thick slices, and a personalized thermoformed mask with 5 attachment points.Preoperative imaging was merged with the planning CT scan to guide the contouring of this surgically reshaped area.Target volumes and organs at risk were delineated according to the different expert recommendations (12)(13)(14)(15)(16)(17).Three clinical target volumes (CTV) were typically defined.CTV1 (59.4 to 60 Gy) was defined as the preoperative tumor bed with a margin (1 to 2 cm), and manually adjusted according to anatomical barriers.CTV2 (54 Gy) was defined as subclinical tumor sites at risk, according to the risk of tumor involvement (14-16), and as prophylactic nodal irradiation, following guidelines (12,13,15).CTV3 (66 Gy) was occasionally identified, in cases of ENE and/or positive margin.Planning target volumes (PTV) related to positioning errors and movements were obtained by adding a 4 mm margin around the CTVs.Treatment was delivered in 30-33 fractions.The treatment planning system was Eclipse® (Varian Medical Systems).Treatment plans followed the recommendations of the International Commission of Radiation Units report n°83 (18).The treatment was delivered using a Clinac IX® or Novalis TX® (Varian Medical Systems) linear accelerators delivering 6-MV photons, with daily position control by KV/KV beams or CBCT.

Follow-up
Weekly evaluations were performed by the radiation oncologist for all patients during radiation treatment.The first post-treatment follow-up was at 3 months after radiation completion.Then, every 3 months for the first and the second year, alternating surgeon and radiation oncologist, and at least twice a year for up to 5 years, and thereafter yearly.A follow-up imaging was performed at 3 months and then annually.

Recurrences
Local and regional recurrences were confirmed via radiologic imaging (i.e.progression in subsequent images or high SUV on PET imaging) or via pathology specimens (i.e. from surgical biopsy).Diagnostic contrast-enhanced CT and/or PET/CT or MRI documenting the initial evidence of local recurrence were investigated.Radiologically evident recurrence volumes were manually segmented and reviewed by four experienced radiation oncologists (CM, JMO, JMI and JB).The corresponding original planning CTs were identified and the original plans were restored.Recurrence CT was co-registered with initial planning CT using a deformable image registration (Aria with MIRS application, version 2.1, Varian Medical Systems) (20,21).The recurrence volume was transferred to the initial planning CT and was subsequently deformed according to the deformable co-registration.A clinical validation was carried out by the radiation oncologists.The most likely point of origin of the recurrence was defined clinically by the radiation oncologists, based on their knowledge of anatomy and cancer spread pathways according to Due et al. (22,23).If the point of origin of the recurrence was outside the initial target volume, recurrence was considered to be "outfield"; if the point of origin of the recurrence was inside the initial target volume, recurrence was considered to be "infield"; and if the point of origin of the recurrence was on the boundary of the initial target volume, recurrence was considered to be "marginal".

Statistical analysis
Groups defined by initial tumor localization were compared using Fisher's exact test and the Wilcoxon-Mann-Whitney test.The Kaplan-Meier method was used to calculate survival curves.The last day of radiation therapy was used as time zero.Comparisons between survival curves were made using the log-rank test.Median follow-up was estimated using the reverse Kaplan-Meier method.Factors associated with survival were analyzed using univariate Cox regression models followed by penalized multivariate models, obtained by including all variables with a pvalue <.05 in the univariate analysis and model selection with the LASSO method.All analyses were performed using R statistical software version 4.1.0(R-Project, GNU GPL).P-values under 0.05 were considered significant.

Results
Local, regional and loco-regional control The median follow-up was 33 months.During follow-up, 26 patients (16%) developed loco-regional recurrences: 12 local, 9 regional, and 5 both local and regional (Table 2).
The 1 and 2-year local control rates were 93% and 90% respectively for the overall population.For oral cavity cancers, the 2-year local control rate was 85.1% vs 96.7% for oropharyngeal cancers (p=0.031).Higher tumor stages (T1-2 vs T3-4; p< 0.001) and presence of PNI (p<0.001) were predictive factors for poorer local control in univariate and multivariate analysis (p=0.03 and p=0.01 respectively) (Table 3).
The 1 and 2-year regional control rates were 93.1%.A number of lymph node over 3 was the only predictive factor for a poorer regional control in univariate and multivariate analysis (p=0.009 and p=0.006 respectively) (Table 3).

Local and regional patterns of recurrence
Seventeen patients (10%) developed a local recurrence and 13 patients (8%) a regional recurrence, of whom 5 patients had both a local and regional recurrence.The initial characteristics and patterns of recurrence are described in Table 2.

Discussion
IMRT/VMAT has been increasingly used over the last two decades for the treatment of head and neck cancers, and is today the gold standard technique in radiation therapy for these cancers.However, the data regarding the outcomes associated with IMRT/ VMAT in the post-operative setting for oral cavity and oropharyngeal cancers is very limited (24-31).Thus our series, despite its relatively small number of patients (n=167), is one of the largest reported to date.The outcomes reported in our series are in line with those reported in the literature (25,26,29,(31)(32)(33)(34) (Table 4).We found that postoperative VMAT reached high rates of local and loco-regional control.We found that the presence of ENE, despite present-day radiochemotherapy techniques, remains a major issue.
There are a few limitations to our study that need to be highlighted.Potential biases, inherent in any retrospective analysis, could have affected the results of this study.Because of the retrospective nature of the study, certain data missing in the medical files could not be assessed for all patients.For example, the depth of invasion for oral cavity cancers was often missing, not allowing to use the latest UICC classification.The same issue was faced regarding HPV status, which was not available for all patients, particularly those treated the earliest in the cohort.We also found that the collection of all toxicities were not robust enough to allow good quality interpretation of the data, so we only focused on the oncological outcomes.This series was also single-center.However, all patients were treated in the same institution with surgery and post-operative radiotherapy in fairly homogeneous manner for both dose prescription and delineation.Concerning local recurrences, during follow-up only 17 patients (10%) developed a local recurrence with actuarial 1 and 2-year local control rates of 93% and 90% respectively.The vast majority of these local recurrences were found to be infield.Higher tumor stages and presence of PNI were the only predictive factors in multivariate analysis for poorer local control.R1 margins were not found to be predictive factors for local control.This is in line with various recent reports that have also found that R1 margins were no longer a factor of poorer local control since the emergence of radiochemotherapy (24, 27, 29, 35).It seems that the negative impact of R1 margins has been fully negated by using higher radiotherapy doses (usually 66Gy) and radiochemotherapy.However, this does not seem to be the case for ENE.Indeed, in our series, the presence of ENE was found to be a prognostic factor for poorer DFS, metastasis-free survival, and OS.A recent series of 439 patients with head and neck SCC (all localizations) treated with postoperative radiotherapy also reported the negative prognostic value of ENE despite the use of radiochemotherapy (35).This finding highlights the need to find new strategies for patients with ENE treated with postoperative radiochemotherapy, as in the ongoing NIVOPOSTOP trial testing

B A
Metastasis-free survival among (A) the entire population, and (B) according to the presence of extranodal extension.
the addition of Nivolumab to standard cisplatin-based chemoradiation (NCT03576417).
We also found that oral cavity cancers generally had poorer outcomes than oropharyngeal cancers, with 2-year LC rates of 85.1% vs 96.7% (p=0.031), and 2-year OS rates of 77.3% vs 83.8% (non-significant, probably due to a lack of statistical power).This is in line with previously reported series (25,29,36).
Regarding chemotherapy, 72 patients (43%) were treated with radiotherapy combined with chemotherapy.The local control and OS rates for these high-risk patients were similar to those for patients with a lower risk of recurrence, treated without concomitant chemotherapy.It is possible that without concomitant chemotherapy the outcome among high-risk patients would have been worse (29).The total number of failures in this series is however too small to enable any robust calculations between subgroups.

Conclusion
Our outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are very encouraging, with high rates of loco-regional control (85.6% at 2 years).However, the management of ENE still seems challenging, as these events were identified as highly unfavorable prognostic factors.-LC recurrence: T3-T4 stage, ENE + -LR recurrence: T3-T4, time from surgery to RT, PNI -OS: T3-T4 stage, ENE + OC oral cavity, OP, oropharynx, LC, local control, LRC, loco-regional control, OS, overall survival, NR, not reported, DOI, depth of invasion, PY, pack-year, R1, positive margins.
FIGURE 1Loco-regional control among (A) the entire population, and (B) according to tumor staging, (C) the presence of perineural invasion, and (D) Time from surgery to radiotherapy.

3 4
FIGURE 3Disease-free survival among (A) the entire population, and (B) according to tumor staging, and (C) the presence of extranodal extension.

TABLE 1
Patient and disease characteristics.

TABLE 2
Prognostic and predictive factors.

TABLE 3
Initial characteristics and analysis of the patients who developed a local and/or regional recurrence.

TABLE 3 Continued
R0=negative margin, ENE +, extranodal extension; ENE -, positive node without extranodal extension; N -, no positive node; Surgery -RT interval, interval between surgery and the first day of radiotherapy.